4-70523877-T-C

Position:

• chr4-70523877-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The ENST00000339336.9(AMTN):​c.148T>C​(p.Ser50Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00614 in 1,613,634 control chromosomes in the GnomAD database, including 310 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.022 (120 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (190 hom.)
• Consequence: AMTN ENST00000339336.9 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.25

Genes affected

AMTN (HGNC:33188): (amelotin) The mineralized portions of teeth, the dentin and enamel, are formed by mesenchyme-derived odontoblasts and epithelium-derived ameloblasts, respectively. As ameloblasts differentiate, they deposit specific proteins necessary for enamel formation, including amelogenin (AMELX; MIM 300391), enamelin (ENAM; MIM 606585), and ameloblastin (AMBN; MIM 601259), in the organic enamel matrix. Amelotin is specifically expressed in maturation-stage ameloblasts (Iwasaki et al., 2005 [PubMed 16304441]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030688941).
• BP6: Variant 4-70523877-T-C is Benign according to our data. Variant chr4-70523877-T-C is described in ClinVar as [Benign]. Clinvar id is 3042027.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.07 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AMTN	NM_212557.4	c.148T>C	p.Ser50Pro	missense_variant	4/9	ENST00000339336.9	NP_997722.1
AMTN	NM_001286731.2	c.145T>C	p.Ser49Pro	missense_variant	4/9		NP_001273660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AMTN	ENST00000339336.9	c.148T>C	p.Ser50Pro	missense_variant	4/9	1	NM_212557.4	ENSP00000341013	P4
AMTN	ENST00000504451.1	c.145T>C	p.Ser49Pro	missense_variant	4/9	1		ENSP00000422452	A2

Frequencies

GnomAD3 genomes AF: 0.0224 AC: 3411 AN: 152158 Hom.: 119 Cov.: 32

Gnomad AFR AF: 0.0722

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0410

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0191

GnomAD3 exomes AF: 0.0102 AC: 2570 AN: 251024 Hom.: 69 AF XY: 0.0103 AC XY: 1404 AN XY: 135668

Gnomad AFR exome AF: 0.0719

Gnomad AMR exome AF: 0.00449

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.0385

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000291

Gnomad OTH exome AF: 0.00474

GnomAD4 exome AF: 0.00444 AC: 6491 AN: 1461358 Hom.: 190 Cov.: 30 AF XY: 0.00523 AC XY: 3802 AN XY: 726958

Gnomad4 AFR exome AF: 0.0732

Gnomad4 AMR exome AF: 0.00476

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0369

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000158

Gnomad4 OTH exome AF: 0.00714

GnomAD4 genome AF: 0.0224 AC: 3415 AN: 152276 Hom.: 120 Cov.: 32 AF XY: 0.0224 AC XY: 1666 AN XY: 74458

Gnomad4 AFR AF: 0.0721

Gnomad4 AMR AF: 0.0106

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0408

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.00436 Hom.: 35

Bravo AF: 0.0246

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0769 AC: 339

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.0118 AC: 1436

Asia WGS AF: 0.0210 AC: 73 AN: 3476

EpiCase AF: 0.000383

EpiControl AF: 0.000476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

AMTN-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 19, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.015	T;.
Eigen	Benign	-0.080
Eigen_PC	Benign	0.038
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.57	T;T
MetaRNN	Benign	0.0031	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;.
MutationTaster	Benign	0.68	N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Benign	0.064
Sift	Uncertain	0.027	D;D
Sift4G	Benign	0.22	T;T
Polyphen		0.36	B;B
Vest4		0.20
MPC		0.45
ClinPred		0.029	T
GERP RS		3.9
Varity_R		0.62
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs34803339; hg19: chr4-71389594;